Methamphetamine (MA) dependence causes devastating personal and public health consequences, particularly in the Western and Midwestern United States (SAMHSA Office of Applied Statistics 2005). Behavioral therapies help some persons reduce or eliminate their use of the drug (Lee and Rawson 2008), but there are no medications approved for the treatment of MA abuse (Vocci and Appel 2007). The development of one or more medications to reduce MA abuse when implemented with evidence-based behavioral and counseling interventions would have obvious public health significance. As noted in PA-07-333, Medications Development for the Treatment of Amphetamine and Amphetamine-Like Related Disorders, this application seeks funding to conduct an initial safety interaction trial of ibudilast (a.k.a. AV411), a non-selective phosphodiesterase inhibitor that has activity as an attenuator of CNS glial activation. Recent research suggests that glial cells may be important in modulating the rewarding properties of drugs of abuse including MA (Vijayaraghavan 2009) and that MA-induced glial activation may contribute to MA's neurotoxicity and associated cognitive dysfunction via glial cell secretion of pro-inflamatory cytokines (Narita, Suzuki et al. 2008). Therefore, we propose testing a novel approach to pharmacologic treatment of MA dependence: amelioration of MA-related cognitive dysfunction/degeneration via suppression of MA-induced glial activation. The proposed study is a Phase I clinical trial that will utilize a randomized double-blind, placebo-controlled within-subject crossover design to determine safety and tolerability and subjective and reinforcing effects of MA in 12 non-treatment seeking MA-dependent volunteers treated with ibudilast (20mg BID and 50mg BID) and placebo. The study will address the following Specific Aims: (1) to determine whether ibudilast (20 mg BID or 50 mg BID) alters the cardiovascular response to IV methamphetamine;(2) to determine whether ibudilast (20 mg BID or 50 mg BID) alters the subjective effects of IV methamphetamine;(3) to determine whether ibudilast (50 mg BID) alters the reinforcing effects of IV methamphetamine;and (4) to determine whether ibudilast alters the pharmacokinetics of IV methamphetamine. Exploratory neurocognitive and pharmaco- genetic analyses will also be performed. The team assembled at UCLA and Harbor-UCLA has extensive expertise in efforts to develop pharmacotherapies for MA abuse and/or dependence. Results of this study will provide the safety-interaction data required before a Phase II clinical trial to assess the efficacy of ibudilast for treatment of MA dependence can be performed. PUBLIC HEALTH RELEVANCE: In Los Angeles County, methamphetamine accounts for more admissions to publicly funded treatments than any other substance, including alcohol and so there is a significant public health need for medications that could optimize outcomes of behavioral therapies for dependent individuals seeking abstinence from methamphetamine. This trial will collect data describing the safety of a potential new treatment, ibudilast (a non-selective phosphodiesterase inhibitor), at two doses (20 mg BID and 50 mg BID) in the presence of 30 mg methamphetamine delivered intravenously. These interaction data are necessary before moving forward with trials of ibudilast in outpatient settings.